Myotonic Dystrophy type 1 (DM1) primarily affects skeletal muscle causing muscle wasting, weakness and myotonia. The most severe, congenital form of DM1 (CDM1) affects children delaying maturation of myofibers. DM1 is associated with expansion of CTG repeats that cause DM1 pathology through accumulation of CUGn RNA. CUG repeats misregulate RNA-binding proteins, including CUGBP1. CUGBP1 is a multifunctional protein which regulates translation, RNA stability and splicing. The translational function of CUGBP1 is essential for normal myogenesis. In normal muscle, cdk4 phosphorylates CUGBP1 at S302. Ph-S302- CUGBP1 (further called CUGBP1Act) interacts with the initiation translation factor eIF2 and activates translation of mRNAs, encoding proteins important for myogenesis. In DM1, CUG repeats reduce levels of cyclin D3 that leads to the elevation of un-phosphorylated S302-CUGBP1 (further called CUGBP1Sup). CUGBP1Sup inhibits translation of mRNAs by trapping them into stress granules. These data suggested that the increase of CUGBP1Sup is the major cause of delayed differentiation in DM1 myogenesis. Searching for the mechanisms of the reduction of cyclin D3 in DM1, we found that the active glycogen synthase kinase 3? (GSK3?) is increased in DM1 muscle biopsies and in muscle of the DM1 mouse model (HSALR mice). Therefore, we hypothesize that the increase of active GSK3? in DM1 reduces cyclin D3-cdk4 pathway leading to accumulation of CUGBP1Sup. CUGBP1Sup inhibits translation of mRNAs that are normally activated by CUGBP1Act. Our hypothesis is that this leads to the delay of myotube fusion reducing myogenesis in CDM1 and reducing muscle regeneration in adult form of DM1. In support of this hypothesis, we show that the inhibition of GSK3? improves histopathology and muscle strength in HSALR mice. To determine the role of CUGBP1Sup in myogenesis in vivo, we have generated S302A CUGBP1 knock-in mice. Skeletal muscle of these mice is characterized by the variability of myofiber size, fibrosis with occasional degenerated fibers and reduction of muscle strength. We will determine if muscle degeneration and muscle weakness in S302A ki mice progress with age (Aim 1). To define the molecular mechanisms by which CUGBP1Sup causes a delay of myogenesis, a set of mRNAs, mis-regulated by CUGBP1Sup in skeletal muscle of S302A ki mice will be identified. We found that CUG repeats increase amounts of GSK3? phosphorylated at Y216. It is known that autophosphorylation of Y216 activates and stabilizes GSK3?? Therefore, Aim 2 will examine if CUG repeats stabilize GSK3? through auto-phosphorylation of GSK3?? In Aim 3, we will treat HSALR mice with siRNA to GSK3? and with inhibitors of GSK3? and examine if this inhibition of GSK3? activity prevents muscle pathology in young mice and reverses muscle abnormalities in adult mice. In summary, these studies will generate a basis for the correction of a delay of myogenesis in patients with DM1.

Public Health Relevance

Myotonic Dystrophy type 1 is characterized by a delay of myogenesis that causes muscle immaturity in newborn children with DM1 and causes a delay of muscle regeneration in patients with adult form of disease. We propose to apply basic science expertise to define the mechanism of muscle immaturity and mechanisms of a delay of muscle regeneration in DM1 with the goal to develop approaches for the clinical therapy of patients with DM1.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Jones, Karlie; Wei, Christina; Schoser, Benedikt et al. (2015) Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5. Proc Natl Acad Sci U S A 112:8041-5
Bachinski, Linda L; Baggerly, Keith A; Neubauer, Valerie L et al. (2014) Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies. Neuromuscul Disord 24:227-40
Hong, Il-Hwa; Lewis, Kyle; Iakova, Polina et al. (2014) Age-associated change of C/EBP family proteins causes severe liver injury and acceleration of liver proliferation after CCl4 treatments. J Biol Chem 289:1106-18
de Haro, Maria; Al-Ramahi, Ismael; Jones, Karlie R et al. (2013) Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy. PLoS Genet 9:e1003445
Meola, Giovanni; Jones, Karlie; Wei, Christina et al. (2013) Dysfunction of protein homeostasis in myotonic dystrophies. Histol Histopathol 28:1089-98
Timchenko, Lubov (2013) Molecular mechanisms of muscle atrophy in myotonic dystrophies. Int J Biochem Cell Biol 45:2280-7
Jones, Karlie; Timchenko, Lubov; Timchenko, Nikolai A (2012) The role of CUGBP1 in age-dependent changes of liver functions. Ageing Res Rev 11:442-9
Jones, Karlie; Wei, Christina; Iakova, Polina et al. (2012) GSK3β mediates muscle pathology in myotonic dystrophy. J Clin Invest 122:4461-72
Jones, Karlie; Jin, Bingwen; Iakova, Polina et al. (2011) RNA Foci, CUGBP1, and ZNF9 are the primary targets of the mutant CUG and CCUG repeats expanded in myotonic dystrophies type 1 and type 2. Am J Pathol 179:2475-89
Iakova, Polina; Timchenko, Lubov; Timchenko, Nikolai A (2011) Intracellular signaling and hepatocellular carcinoma. Semin Cancer Biol 21:28-34

Showing the most recent 10 out of 31 publications